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PDB Research Experience Summer Intern Presentation August 3, 2009 Heidi Chen Jane Hand Mira Patel

PDB Research Experience Summer Intern Presentation August 3, 2009 Heidi Chen Jane Hand Mira Patel Mike Ticchio. Outline. Peptide Reference Dictionary Antibiotics (Done) ‏ Combined Inhibitors (Done) ‏ Poly/Split Inhibitors Second Life Personal Reflections. Where we left off from.

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PDB Research Experience Summer Intern Presentation August 3, 2009 Heidi Chen Jane Hand Mira Patel

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  1. PDB Research Experience Summer Intern Presentation August 3, 2009 Heidi Chen Jane Hand Mira Patel Mike Ticchio

  2. Outline Peptide Reference Dictionary Antibiotics (Done)‏ Combined Inhibitors (Done)‏ Poly/Split Inhibitors Second Life Personal Reflections

  3. Where we left off from... • Finalized Antibiotic Spreadsheet A + B • Finished the Combined Inhibitor List • 250 Inhibitors + PDB instances • Analyzed a total of 394 PDB instances 2S,3S MEG (2S,3R)-3-METHYL-GLUTAMIC ACID LME (3R)-3-METHYL-L-GLUTAMIC ACID

  4. Spreadsheet A Replaced SMILES with InChi Key

  5. Spreadsheet B

  6. Issues • Duplicate CCIDs • Discrepancies with SciFinder • Carbons

  7. A62095 Chemical Component Dictionary vs. SciFinder CAS RN: 144499-88-7 Molecular Formula: C28H53N3O6 CCID: 0ZL Molecular Formula: C29H55N3O6 isobutyl

  8. A62095 isobutyl Diagram in Paper L. Chen et al. 1992

  9. Comparison with another inhibitor 0ZL Seq: 0AG LEU XAO 0QF Seq: PHE GLY XAO SOT SCC isobutyl CAS RN: 127953-15-5 Molecular Formula: C31H52N4O7S2 CCID: 0QF Molecular Formula: C31H52N4O7S2

  10. A66702 Paper Diagram vs. SciFinder CAS RN: 144499-89-8 isobutyl L. Chen et al. 1992

  11. A61963 Paper Diagram vs. SciFinder CAS RN: 105882-31-7 isobutyl L. Chen et al. 1992

  12. Overall Comparison

  13. Renin PDB 1BIM L. Tong et al. 1995 • Secreted by kidneys • Mediates extracellular volume and arterial vasoconstriction • Role in Renin-Angiotensin-Aldosterone Axis/Renin-Angiotensin System (RAS) • Hydrolyzes angiotensinogen into angiotensin I

  14. Renin Inhibitor • Decreases blood pressure PDB: 1BIM L. Tong et al. 1995

  15. Renin Inhibitor • Extensive H-bonding PDB: 1BIM L. Tong et al. 1995

  16. Top: Saquinavir with HIV-1 protease Bottom: Catalytic Asp25 highlighted HIV-1 Protease and Reverse Transcriptase Inhibitors PDB 1lwc Stammers et al PDB 2nmz Weber et al Nevirapine with HIV-1 reverse transcriptase

  17. C peptides HIV Entry Pathway Adapted from Kay et al, 2007 and Eckert et al, 1999

  18. D-Peptide Inhibitors IQN17:2K-PIE 1 inhibitor complex Kay et al, 2007 Kay et al, 2007 Mechanism: Targets the hydrophobic gp41 pocket PDB 2r5b Kay et al, 2007

  19. PIE 7 PIE 7 2K-PIE1 vs. PIE 7 Kay et al, 2007 dTyr7 dAsp6 dAsp6 Gly-575 dGly3 PDB 2r5b Kay et al, 2007 Gln-575 dgly3 Trp-571 Trp-571

  20. Thrombin • Coagulation factor in the coagulation cascade • Converts fibrinogen into insoluble strands of fibrin • Activates Factor V and Factor XIII • Promotes platelet activation Goodsell, Mol. of the Month Adapted from http://en.wikipedia.org/wiki/Coagulation#The_coagulation_cascade

  21. PPACK • D-Phe-Pro-Arg-CMK • Also known as FPRCK • Well-documented inhibitor of Thrombin • Synthetic and highly selective Google Image Search

  22. PPACK Interaction • Thrombin has a hydrophobic cage • Active site has polar residues PDB ID 1dwe, Banner et. al 1991 • PPACK binds to Histidine57 and Serine195 PDB ID 1dwe, Banner et. al 1991

  23. Other Thrombin Inhibitors BMS-183507 FM19 PDB ID 1hdt, Tabernero et al 1995 Banner et. al PDB ID 3bv9, Nieman et al 2008

  24. Coronavirus Main Proteinase 3CLpro • human coronavirus causes Severe Acute Respiratory Syndrome (SARS) • the main proteinase (3CLpro ) is target for therapy • high degree of conservation in substrate binding sites of human and porcine coronavirus proteinases

  25. Porcine Coronavirus Proteinase • catalytic activity inhibited by hexapeptidyl chloromethyl ketone (CMK) inhibitor Anand, K. et al. 2003 PDB: 1P9U (X RAY)

  26. Proteinase Active Site • cysteine protease • hexapeptidyl CMK possible inhibitor of human coronavirus protease • PDB: 1P9U

  27. Poly/Split Inhibitors • not to be combined • 373 PDB instances • capture functions, synonyms from primary citation and references

  28. Poly/Split Inhibitors • Sequence Check • BLAST search: up to top 5 Uniprot matches • check for consistency between primary citation, PDB file, and Uniprot • Norine • nonribosomal peptide database

  29. BLAST- Uniprot Spreadsheet

  30. Second Life • Our Beautiful Sculpties • Weekly Building Workshops • Building Basics (Week 1) • Basic Script Writing (Week 2) • Orac (Week 3) • Other methods of rezzing • Hiro’s Protein-rezzing Kit • Monolith

  31. Second Life • Plans for the Future • Build a pedestal with buttons • Use Hiro’s protein rezzing kit to build the heme of myoglobin • Write notecards for our sculpties

  32. Thanks! • Thank you to Dr. Helen Berman, Dr. Shuchi Dutta, Dr. Maggie Gabanyi, Dr. John Westbrook, Dr. Terry Stouch, Dr. Zukang Feng, Hyunmi Sun and James Chun • Any questions or comments?

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